Inappropriate smooth muscle activation is believed to be involved in urinary incontinence and in many other conditions and diseases including, hypertension, asthma, peripheral vascular disease, right heart failure, congestive heart failure, angina, ischemic heart disease, cerebrovascular disease, renal colic, disorders associated with kidney stones, irritable bowel syndrome, male-patter baldness, premature labor, impotence and peptic ulcers.
It is known that urinary incontinence can occur because uncontrolled or unstable bladder contractions arise in excitable bladder tissue, so-called overactive bladder. Existing treatments for urinary incontinence rely largely on drugs that were originally developed for other indications. One group of such drugs includes the calcium-channel blockers, an example of which is nifedipine (4-(2′-nitrophenyl)-2,6,-dimethyl-3,5-dicarbomethoxy-1,4-dihydropyridine). Such drugs were originally developed and are primarily used as antianginal or antihypertensive cardiovascular agents.
Nifedipine is a member of a class of compounds known as dihydropyridines. Structural requirements for calcium blocking activity by dihydropyridines are now well established. Active compounds described in Chapter 14.1 of the medicinal chemistry text book, Comprehensive Medicinal Chemistry, Volume 3, Edited by John C. Emmett (Pergamon Press 1990), possess a 1,4-dihydropyridine ring with an aryl group at the 4-position and ester groups at the 3- and 5-positions.
A group of 1,4-dihydropyridine derivatives that are said to have strong muscular spasmolytic effects, are disclosed in German Patent DE 2003148. Such compounds include certain 4,6,7,8-tetrahydro-5(1H)-quinolones that possess an ester or keto group at the 3-position. A wide spectrum of pharmacological actions are disclosed for the compounds including strong muscular spasmolytic effects which become evident in the smooth musculature of the gastrointestinal tract, the urogenital tract and the respiratory system. Effects on the heart are also disclosed (a “heart-relieving” effect) with a reduction of the blood pressure of normotonic and hypertonic animals.
Vitolinya et al, Khim.-Farm. Zh., 15(1), 39–42, 1981, have reported that 3-cyano-4-phenyl-2,7,7-trimethyl-4,6,7,8-tetrahydro-5(1H)-quinolone blocks the spasmogenic effect of both acetylcholine and barium chloride on intestinal smooth muscle and has hypotensive properties.
S. M. Jain et al, Indian Journal of Chemistry, Volume 30B, November, 1991, pages 1037–1040, discloses the synthesis and pharmacological screening of certain 9-(substituted phenyl)-1,8-(2H,5H-)-acridinediones. The compounds are disclosed by Jain et al, as having varying degrees of hypotensive, anti-inflammatory and anti-implantation activities.
It is known that potassium channel opening compounds can relax smooth muscle tissue by functioning to open potassium channels. For example, D. A. Nurse et al, British Journal of Urology, (1991), 68, 27–31, disclose that a well known potassium channel opener, cromakalim ((−)-6-cyano-3,4-dydihydro-2,2-dimethyl-trans-4,(2-oxo-1-pyrrolidinyl)-2H-benzo[b]pyran-3-ol), has been found to be effective in a preliminary clinical trial for the treatment of urinary incontinence. Accordingly, it is believed that compounds that function to open potassium channels in bladder cells and thereby relax bladder smooth muscle tissue, can prevent or ameliorate uncontrolled bladder contractions which can cause urinary incontinence. It is also known that urinary incontinence can be caused by uncontrolled or unstable bladder smooth muscle contractions and that potassium-channel opening compounds can cause relaxation of smooth muscle and excitable bladder tissue. Accordingly, U.S. Pat. No. 5,455,253 discloses a group of potassium-channel opening compounds, that is, 4,6,7,8-tetrahydro-5(1H)-quinolones, their use in the treatment of urinary incontinence in mammals (including man), and methods for preparing the compounds and pharmaceutical compositions containing the compounds.